Recommended Approaches for Pharmacokinetic Natural Product-Drug Interaction Research: a NaPDI Center Commentary

Abstract

Sales of botanical dietary supplements and other purported medicinal natural products (NPs) have escalated over the past ∼25 years, increasing the potential for NPs to precipitate clinically significant pharmacokinetic interactions with U.S. Food and Drug Administration-approved medications [NP-drug interactions (NPDIs)]. However, published NPDI studies to date often lack consistency in design, implementation, and documentation, which present difficulties in assessing the clinical significance of the results. Common hurdles include large variability in the admixture composition of phytoconstituents between and within batches of a given NP, limited knowledge on the pharmacokinetics of precipitant NP constituents, and use of animal and/or in vitro models which, in some cases, are not mechanistically appropriate for extrapolation to humans. The National Center for Complementary and Integrative Health created a Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) to address these unmet research needs. The NaPDI Center has two overarching goals: 1) develop Recommended Approaches to guide researchers in the proper conduct of NPDI studies, which will evolve over time concurrent with emerging technologies and new research data, and 2) apply the Recommended Approaches in evaluating four model NPs as precipitants of NPDIs with clinically relevant object drugs. The major objectives of this commentary are to 1) explain the rationale for creating the NaPDI Center; 2) describe the decision trees developed by the NaPDI Center to enhance the planning, rigor, and consistency of NPDI studies; and 3) provide a framework for communicating results to the multidisciplinary scientists interested in the NaPDI Center's interaction projects.

Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Figures

Fig. 1.

Decision tree, part I: addressing challenges 1–3, 5, and 6 (listed in Table 1).

Fig. 2.

Decision tree, part II: addressing challenges 3–5 (listed in Table 1); PBPK, physiologically based pharmacokinetic; PK, pharmacokinetic.

Fig. 3.

Decision tree, part III: addressing challenges 1 and 3–6 (listed in Table 1); AUCNP, AUC in the presence of the natural product; IC50, the concentration of an inhibitor that reduces the velocity of the reaction by half at a single substrate concentration; PBPK, physiologically based pharmacokinetic.